The major objective of this research proposal is to elucidate the mechanism(s) regulating the in vivo switch from fetal to adult hemoglobin formation by using the sheep transplantation model. In this model hemopoietic cells from sheep homozygous for Hb B are transplanted to recipients homozygous for HbA. If there is engraftment of the donor cells, evidence is obtained by the appearance of the donor Hb in the recipient's blood. The sheep transplantation model provides a unique in vivo system for determining whether HbF to HbA switching is accomplished through progenitor cell-environment interaction. Seven series of transplantation experiments will be done for reasons specified in the proposal. In 3 series, fetal hemopoietic cells will be transplanted into adult animals, while in 4 series, adult hemopoietic cells will be transplanted into catheterized pre-switch fetuses. To assess the effect of the new environment on the globin programs of the donor progenitor cells, the phenotypes of hemoglobins will be determined by assaying single cell-origin erythroid colonies. It is expected that these experiments will provide definitive answers to the questions we have posed on the mechanism of HbF switching. We also anticipate that these studies will yield data of significant relevance to the field of transplantation biology.